Neoadjuvant endocrine therapy with or without palbociclib in low-risk patients: a phase III randomized double-blind SAFIA trial.

BACKGROUND: The most prevalent subtype of breast cancer (BC) is luminal hormonal-positive breast cancer. The neoadjuvant chemotherapy regimens have side effects, emphasizing the need to identify new startegies. OBJECTIVE: Analyze the complete pathologic response (pCR) rate and overall response in a low-risk hormone-positive subset of patients receiving neoadjuvant hormone treatment (NAHT) with or without Palbociclib (a CDK4/CDK6 inhibitor) to boost NAHT effectiveness. MATERIALS AND METHODS: Based on the upfront 21-gene Oncotype DX or low-risk Breast Recurrence Score assay (RS™), the SAFIA trial is designed as a prospective multicenter international, double-blind neoadjuvant phase-III trial that selects operable with luminal BC patients that are HER2-negative for the induction hormonal therapy with Fulvestrant 500 mg ± Goserelin (F/G) followed by randomization of responding patients to palbociclib versus placebo. The pCR rate served as the study's main outcome, while the secondary endpoint was a clinical benefit. RESULTS: Of the 354 patients enrolled, 253 initially responded and were randomized to either F/G fulvestrant with palbociclib or placebo. Two hundred twenty-nine were eligible for the evaluation of the pathologic response. No statistically significant changes were observed in the pCR rates for the patients treated with the F/G therapy with placebo or palbociclib (7% versus 2%, respectively) per the Chevallier classification (Class1 + Class2) (p = 0.1464) and 3% versus 10% assessed per Sataloff Classification (TA, NA/NB) (p = 0.3108). Palbociclib did not increase the rate of complete pathological response. CONCLUSION: Neoadjuvant hormonal therapy is feasible in a selected population with a low RS score of < 31 CLINICAL TRIAL: NCT03447132.

Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer.

Background: There is no standard treatment after progression on second-line chemotherapy for metastatic breast cancer (MBC). We compared vinflunine with physician's choice of alkylating agent (AA) for patients with heavily pretreated MBC. Patients and methods: In this open-label phase III trial, patients with MBC were included if they had received at least two prior chemotherapy regimens for MBC and had received anthracycline, taxane, antimetabolite and vinca alkaloid therapy. Patients were no longer candidates for these chemotherapies because of resistance and/or intolerance. Patients were randomised to either vinflunine 280 mg/m2 intravenously every 3 weeks (q3w) or AA monotherapy q3w. Stratification factors were performance status, number of prior chemotherapy lines for MBC, disease measurability and study site. The primary end point was overall survival (OS). Results: A total of 594 patients were randomised (298 to vinflunine, 296 to AA). There was no difference between treatment arms in OS (hazard ratio 1.04, P = 0.67; median 9.1 months for vinflunine versus 9.3 months for AA), progression-free survival (hazard ratio 0.94, P = 0.49; median 2.5 versus 1.9 months, respectively) or overall response rate (6% versus 4%, respectively). However, the disease control rate was significantly higher with vinflunine than AA (44% versus 35%, respectively; P = 0.04). The most common adverse events (any grade) were haematological and gastrointestinal disorders and asthenia in both arms. The most common grade 3/4 adverse events were neutropenia (19% versus 11% with vinflunine versus AA, respectively) and asthenia (10% versus 4%). Conclusions: Vinflunine 280 mg/m2 q3w did not improve OS compared with the physician's choice of AA as third- or later-line therapy for MBC. Vinflunine demonstrated an acceptable safety profile, suggesting that vinflunine 320 mg/m2 merits evaluation. ClinicalTrials.gov: NCT01091168.

Multicentric neoadjuvant pilot Phase II study of cetuximab combined with docetaxel in operable triple negative breast cancer.

Systemic therapy for triple negative breast cancer (TNBC) is mostly based upon chemotherapy. Epithelial Growth Factor Receptor (EGFR) is overexpressed in around 50% of TNBC and may play a role in its pathogenesis. Consequently, we performed a multicentric pilot Phase II neoadjuvant trial of cetuximab (anti-EGFR antibody) combined with docetaxel for patients with operable, Stage II-III TNBC. Therapy consisted of weekly cetuximab (first infusion: 400 mg/m(2), then 250 mg/m(2)) combined with six cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Subsequently, all patients underwent surgery. The primary endpoint was pathological complete response (pCR) while clinical response, toxicity and ancillary studies were secondary endpoints. Paraffin-embedded and frozen tumor samples were systematically collected in order to identify predictive biomarkers of efficacy and resistance. From a total of 35 accrued patients, 25 were assessable for pathologic response. The pCR rate was 24% [95% CI: 7.3-40.7]. Complete clinical response rate (cCR) was observed in 22% of cases. Conservative surgery was performed in 75% of patients. Toxicity, mostly cutaneous and hematologic, was manageable. The pre-therapy ratio between CD8+ and FOXP3+ tumor-infiltrating lymphocytes equal or higher than 2.75 was predictive of pCR: 43% versus 0%, p = 0.047. Cetuximab in combination with docetaxel displays a modest activity, but acceptable toxicity as neoadjuvant therapy of operable TNBC. Similarly to previous observations using panitumumab, another anti-EGFR antibody, the immune component of the tumor microenvironment may play an important role in predicting TNBC response to the neoadjuvant therapy.

Multicentric neoadjuvant phase II study of panitumumab combined with an anthracycline/taxane-based chemotherapy in operable triple-negative breast cancer: identification of biologically defined signatures predicting treatment impact.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors for some of which the epithelial growth factor receptor (EGFR) pathway may play an important role. We investigated the efficacy and toxicity of an anti-EGFR antibody (panitumumab) combined with a standard neoadjuvant anthracycline-taxane-based chemotherapy in patients with operable, stage II-III, TNBC. PATIENTS AND METHODS: Treatment in this multicentric neoadjuvant pilot study consisted of panitumumab (9 mg/kg) for eight cycles q.3 weeks combined with four cycles of 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC100: 500/100/500 mg/m(2)) q.3 weeks, followed by four cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Following therapy, all patients underwent surgical resection. Pathologic complete response (pCR) in assessable patients was the main end point while clinical response, toxicity and ancillary studies were secondary end points. Paraffin-embedded and frozen tumor samples were systematically collected with the aim to identify predictive biomarkers of efficacy and resistance in order to select biologically defined subpopulations for potential further clinical development of the anti-EGFR antibody. RESULTS: Sixty patients were included with 47 assessable for pathologic response. The pCR rates were 46.8% [95% confidence interval (CI): 32.5% to 61.1%] and 55.3% [95% CI: 41.1% to 69.5%] according, respectively, to Chevallier and Sataloff classifications. The complete clinical response (cCR) rate was 37.5%. Conservative surgery was carried out in 87% of cases. Toxicity was manageable. The association of high EGFR and low cytokeratin 8/18 expression in tumor cells on one hand and high density of CD8+ tumor-infiltrating lymphocytes on the other hand were significantly predictive of pCR. CONCLUSIONS: Panitumumab in combination with FEC100 followed by docetaxel appears efficacious, with acceptable toxicity, as neoadjuvant therapy of operable TNBC. Several biomarkers could help define large subsets of patients with a high probability of pCR, suggesting a potential interest to further develop this combination in biologically defined subgroups of patients with TNBC. CLINICAL TRIAL NUMBER: NCT00933517.

Prognostic value of initial tumor parameters after metastatic relapse.

Classical prognostic factors of breast cancer are correlated to disease-free survival and overall survival (OS); their precise role is less known on metastatic disease. A total of 511 breast cancer patients without initial metastasis were treated. OS was divided in time to distant recurrence and metastatic survival (MS). Age, Scarff-Bloom-Richardson (SBR) grade, hormone receptor, axillary node involvement, and Nottingham prognostic index predicted MS in univariate analysis. Multivariate analysis retained age, SBR grade, and axillary lymph node involvement as significant independent prognostic factors. Interactions are still present between initial parameters and MS. The clinician has to take into account for treatment choice.

Mastectomy with immediate breast reconstruction after neoadjuvant chemotherapy and radiation therapy. A new option for patients with operable invasive breast cancer. Results of a 20 years single institution study.

PURPOSE: To evaluate the feasability of immediate breast reconstruction (IBR) following mastectomy after neoadjuvant chemotherapy (NACT) and radiation therapy (RT) for operable invasive breast cancer (OIBC), in terms of incidence of local complications, locoregional control and survival. PATIENTS AND METHODS: From 1990 to 2008, 210 patients were treated by NACT, RT and mastectomy with IBR for OIBC. One hundred and seven patients underwent a latissimus dorsi flap with implant (LDI), 56 patients a transverse rectus abdominis musculocutaneous (TRAM) flap, 25 an autologous latissimus dorsi flap (ALD) and 22, a retropectoral implant (RI) reconstruction. RESULTS: Forty-six (21.9%) early events were recorded: 20 necrosis, 9 surgical site infections and 6 haematomas, requiring further surgery in 23 patients. More necrosis were observed with TRAM flap reconstructions (p = 0.000004), requiring more surgical revision than LD reconstructions. Seromas represented 42% of early complications in LD reconstructions. Fifty-five patients presented with late complications (26.2%) with mainly implant complications (capsular contracture, infection, dislocation, deflation) (23.6%), requiring reintervention in 14 cases. There were more delayed surgical revisions in RI reconstructions (p = 0.0005). The 5 years overall and disease-free survival rates were respectively 86.7% and 75.6%. Sixty-four patients presented at least one recurrence (30.5%) with 5 local, 9 locoregional and 54 distant relapses. CONCLUSION: This therapeutic sequence does not seem to increase the IBR morbidity nor alter disease-free and overall survival.

Late lines of treatment benefit survival in metastatic breast cancer in current practice?

Metastatic breast cancer is mostly incurable. Progressively overall survival (OS) has improved but few authors have studied treatment globally versus for each line and demonstrated the interest of chemotherapy (CT) after the third line. We selected recent patients treated during the "taxane/anti-aromatase era" for each line given. 529 received CT and 383 hormonotherapy. OS was assessed; from the date of first metastasis and from Day 1 of each CT line. Median OS was 34.1 months; 226 patients received >3 lines of CT with a steady median OS for late lines, 11.4 months per line (range 10.4-12.6). Clinical benefit after the third line of CT was obtained for 29.2-36.6% of patients. CT lasted 11.7 months "on"versus 20.6 months "off" CT. These results may support the use of more than 3 CT lines; each line can contribute to a longer survival.

Aromatase inhibitors in the management of early breast cancer.

The adjuvant treatment of patients with endocrine-sensitive breast cancer has been dominated for several decades by the gold-standard tamoxifen. Promising results on the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, in advanced disease led to the development of these agents in the treatment of early breast cancer. Recent results consistently show the superiority of these agents over tamoxifen, and the therapeutic strategies of AIs in the adjuvant setting are still being discussed. Various approaches have been evaluated, including the following: 1. upfront 5-year use of an AI instead of tamoxifen for newly diagnosed patients, 2. upfront sequence of tamoxifen followed by an AI (or the inverse) for a total of 5 years, 3. switching to an AI after 2e3 years of tamoxifen for patients presently on tamoxifen (total of 5 years), 4. extended endocrine therapy with an AI after completing 5 years of adjuvant tamoxifen. However, it is unclear whether one of these AI strategies is superior to the other ones. The overall therapeutic index of AIs appears superior to that of tamoxifen, with proven improved efficacy and a better toxicity profile. AIs are less toxic than tamoxifen in terms of thromboembolic disease and gynaecological complications, while musculoskeletal disorders and joint pains are more frequently seen with AIs. This review explores the results of all phase III adjuvant AIs trials available up to December 2007 and is trying to define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.

Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial.

BACKGROUND: The Arimidex (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole with tamoxifen as adjuvant treatment for postmenopausal women with early-stage breast cancer. After an extended follow-up beyond the 5 years of treatment, we aimed to assess the safety, tolerability, and risk-benefit indices of these compounds. METHODS: We analysed postmenopausal women (mean age 64 years [SD 9]) with localised breast cancer randomly assigned to anastrozole (n=3125) or tamoxifen (n=3116). Efficacy measures, including death and risk-benefit indices, were analysed by intention to treat. Safety analyses were based on treatment first received (n=3092 for anastrozole and n=3094 tamoxifen). We calculated a risk-benefit analysis using the two global indices for the Women's Health Initiative and for Disease-Free Survival and Serious Adverse Events. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. FINDINGS: At median follow-up of 68 months (range 1-93), treatment-related adverse events occurred significantly less often with anastrozole than with tamoxifen (1884 [61%] vs 2117 [68%]; p<0.0001), as did treatment-related serious adverse events (146 [5%] vs 277 [9%]; p<0.0001) and adverse events leading to withdrawal (344 [11%] vs 442 [14%]; p=0.0002). Patients given anastrozole had significantly fewer overall events for the Global Index of the Women's Health Initiative (744 [24%] vs 851 [27%]; hazard ratio 0.85 [95% CI 0.77-0.94], p=0.001) and the Global Index of Disease-Free Survival and Serious Adverse Events (1453 [46%] vs 1594 [51%]; 0.88 [0.82-0.94]; p=0.0004). INTERPRETATION: Anastrozole is tolerated better than tamoxifen by postmenopausal women with early-stage breast cancer, and results in fewer serious adverse events. Furthermore, it has a more favourable overall risk-benefit profile and lower recurrence rate than tamoxifen.

A longitudinal prospective study of health-related quality of life in breast cancer patients following high-dose chemotherapy with autologous blood stem cell transplantation.

This prospective longitudinal study examined both short- and long-term changes in health-related quality of life (HRQL) in 52 breast cancer patients with poor prognosis receiving high-dose chemotherapy (HDC) treatment with autologous blood stem cell transplantation (ASCT). HRQL was measured seven times from baseline to 2 years post enrollment with the Functional Living Index-Cancer (FLIC), the EuroQol (EQ-5D), and a quality of life visual analogue scale. The percentage of questionnaires returned at each assessment time ranged from 80 to 92%. All three measures showed a similar pattern of change, with HRQL decreasing following administration of HDC, and returning to baseline levels 8 weeks post HDC. A repeated-measures analysis of variance showed that the FLIC at 2 years was significantly better than baseline (P=<0.0001). Difficulty sleeping, headaches, and decreased sexual interest were the most common symptoms reported in the longer term. Our results have implications for early psychosocial intervention in the care of breast cancer patients with poor prognosis undergoing treatment with HDC and ASCT because such interventions can further improve the quality of their survival.

Advanced breast cancer updates on anastrozole versus tamoxifen.

Results from two studies, the North American trial and the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability (TARGET) trial carried out in Europe/rest of the world comparing 'Arimidex' (anastrozole) 1 mg with tamoxifen 20 mg for treatment of advanced breast cancer in postmenopausal women, have previously been reported individually and as a prospectively combined analysis. For the combined analysis, at a median follow-up of 18.2 months anastrozole was shown to be superior to tamoxifen in terms of time to progression (TTP; P=0.022) in the hormone receptor-positive subgroup. Both treatments were well tolerated; anastrozole was associated with significantly fewer thromboembolic events (P=0.043) and fewer reports of vaginal bleeding. The survival analyses and safety update in the overall population and in the hormone receptor-positive subgroup from the combined data are now available. At a median follow-up of 43 months, 56.0% of patients in the anastrozole group and 56.1% of patients in the tamoxifen group had died. At the cut-off date, 2-year mortality rates were 31.7 and 32.5% with anastrozole and tamoxifen, respectively, in the overall population. Median time to death (TTD) was similar for both treatments (39 months versus 40 months, respectively; hazard ratio (HR) 0.97, lower 95% confidence limit (CL) 0.84). Similar findings were reported in the hormone receptor-positive population. With longer follow-up, both anastrozole and tamoxifen remained well tolerated. Sequencing data showed that patients crossed from anastrozole to tamoxifen or tamoxifen to anastrozole are similar regarding efficacy. In conclusion, these TTP, survival and tolerability data support the use of anastrozole as a first-line therapy of choice in postmenopausal women with advanced breast cancer.

Efficacy of tamoxifen following anastrozole ('Arimidex') compared with anastrozole following tamoxifen as first-line treatment for advanced breast cancer in postmenopausal women.

Anastrozole ('Arimidex') is indicated for the treatment of advanced breast cancer in postmenopausal women. Combined analysis of two international randomised, double-blind trials (n=1021) showed that in patients with hormone receptor-positive tumours, first-line treatment with anastrozole significantly prolonged the time to progression (TTP) compared with tamoxifen (median TTP: 10.7 versus 6.4 months, respectively; P=0.022). Second-line tamoxifen following anastrozole, or vice versa, in this trial population was unblinded. The treatments were crossed over and then efficacy was assessed using a questionnaire. Of 511 patients randomised to anastrozole, 137 (26.8%) received second-line tamoxifen. Questionnaire data were available for 119 patients; 58 (48.7%) gained clinical benefit (CB=complete+partial response (CR+PR)+(stable disease (SD) >/=24 weeks)), while 12 (10.1%) had an objective response (OR=CR+PR). Of 510 patients randomised to tamoxifen, 134 (26.3%) received second-line anastrozole. Questionnaire data from 95 patients showed that 54 (56.8%) gained CB and 7 of the patients gaining CB (7.4%) had an OR. Previous studies showed anastrozole is effective after first-line tamoxifen. These data show that the sequential administration of first-line anastrozole followed by tamoxifen provides effective use of these drugs in the treatment of postmenopausal women with advanced breast cancer.

Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results.

We present an initial survival analysis and an update of the safety data of the North American and Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability (TARGET) double-blind, randomised, multicentre studies which compared anastrozole with tamoxifen as first-line treatment in postmenopausal patients with oestrogen receptor and/or progesterone receptor-positive (ER+/PR+) or receptor-unknown advanced breast cancer (ABC). At a median follow-up of 43.7 months, 56.0% of patients in the anastrozole group and 56.1% of patients in the tamoxifen group had died. The proportion of patients dead at 2 years was 31.1 and 32.0% in the anastrozole and tamoxifen groups, respectively. In the ER+/PR+ subgroup, 55.1 and 55.9% of patients had died and median time to deaths (TTD) were 40.8 and 41.3 months in the anastrozole and tamoxifen groups, respectively. Both agents remained well tolerated, with fewer reports of vaginal bleeding (anastrozole versus tamoxifen, 1.0% versus 2.5%) and thromboembolic events (anastrozole versus tamoxifen, 5.3% versus 9.0%) in the anastrozole group versus the tamoxifen group. Hot flushes and vaginal dryness were reported marginally less in the tamoxifen group compared with the Anastrozole group. Although no improvement in survival was observed, the favourable profile of anastrozole with respect to efficacy (TTP) and tolerability [Cancer 92 (2001) 2247] support the use of anastrozole in advance of tamoxifen as the first-line therapy choice in postmenopausal women with ABC.

Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma.

BACKGROUND: Two randomized, double-blind trials have compared tamoxifen 20 mg daily and the selective, nonsteroidal aromatase inhibitor anastrozole 1 mg daily as first-line therapy for advanced breast carcinoma (ABC) in postmenopausal women. The trials were prospectively designed to allow for combined data analyses. METHODS: The combined study population included 1021 postmenopausal women (median age, 67 years [range, 30-92]) with ABC whose tumors were either estrogen and/or progesterone receptor positive or of unknown receptor status. Primary endpoints were time to progression (TTP), objective response, and tolerability. RESULTS: At a median duration of follow-up of 18.2 months, anastrozole was at least equivalent to tamoxifen in terms of median TTP (8.5 and 7.0 months, respectively; estimated hazard ratio [tamoxifen relative to anastrozole], 1.13 [lower 95% confidence level, 1.00]). In a retrospective subgroup analysis, anastrozole was superior to tamoxifen with respect to TTP (median values of 10.7 and 6.4 months for anastrozole and tamoxifen, respectively, two-sided P = 0.022) in patients with estrogen and/or progesterone receptor positive tumors (60% of combined trial population). In terms of objective response, 29.0% of anastrozole and 27.1% of tamoxifen patients achieved either a complete response (CR) or a partial response (PR). Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 57.1% and 52.0% for anastrozole and tamoxifen, respectively. Both anastrozole and tamoxifen were well tolerated. Anastrozole led to significantly fewer venous thromboembolic (P = 0.043; not adjusted for multiple comparisons) events, and vaginal bleeding was reported in fewer patients treated with anastrozole than with tamoxifen. CONCLUSIONS: In postmenopausal women with hormonally sensitive ABC, anastrozole should be considered as the new standard first-line treatment.

Taxane/anthracycline combinations: setting a new standard in breast cancer?

Among the novel chemotherapeutic drugs introduced in the 1990s, the taxanes have emerged as the most powerful compounds in breast cancer. Both compounds, paclitaxel and docetaxel, have been evaluated in metastatic settings before adjuvant trials proceeded. Docetaxel was shown in several phase III trials to be superior, particularly in terms of survival, for salvaging polychemotherapies after failure of prior chemotherapy, including that with anthracyclines. A benefit of docetaxel was also reported when compared with doxorubicin after failure of alkylating agents. In phase III trials paclitaxel was reported to be as efficacious over 24 hours as doxorubicin 60 mg/m(2), while paclitaxel was significantly inferior to doxorubicin 75 mg/m(2) over 3 hours and was close to CMF in another trial. The role of taxanes in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging. Following several phase II studies, a phase III trial showed the significant superiority of docetaxel/doxorubicin (AT) versus doxorubicin/cyclophosphamide (AC) in terms of response and time to progression. In several phase II studies with paclitaxel (3 hours), anthracyclines in the metastatic setting showed high efficacy but produced cardiac toxicity related to a pharmacokinetic interaction between the two agents. This finding led to the implementation of metastatic strategies (phase III trials) aimed at avoiding the pharmacokinetic interaction, while the adjuvant strategies with paclitaxel focused primarily on the sequential approach (AC followed by paclitaxel). In contrast, adjuvant strategies with docetaxel/anthracycline-based programs were implemented following both sequential and combination approaches.

New adjuvant strategies for breast cancer: meeting the challenge of integrating chemotherapy and trastuzumab (Herceptin).

Improvements in breast cancer treatment will arrive with better understanding of its biology and through biologically oriented therapeutic interventions as well as better identification of patient populations susceptible to benefit from classical therapies (endocrine and chemotherapy). Among the new chemotherapies, the taxanes have emerged as powerful agents in the treatment of metastatic breast cancer and a strong emphasis has been pursued into their development in the adjuvant setting. Two generations of adjuvant pivotal trials with taxanes have been developed. The first generation compared taxane/anthracycline regimens to nontaxane combinations or sequence regimens. The second generation of trials is presently being performed and contains taxanes in both arms, comparing their use in combination or in sequence. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is the first biologic modifier with significant activity in advanced breast cancer patients amplifying the HER2 gene. As a consequence of these results, including improved survival in the metastatic setting, this agent has been very quickly considered for adjuvant development. However, the significant cardiac toxicity observed with trastuzumab/anthracycline combinations has led to two main strategies for integrating trastuzumab in the adjuvant setting: (1) addition of trastuzumab to mostly anthracycline-based programs (sequential approach); and (2) biology-oriented strategy based on synergism between trastuzumab and chemotherapy agents. Large-scale clinical research programs are presently being developed and will create a challenge for clinical researchers. The adequate scientific hypothesis, related to the pivotal studies of trastuzumab in the adjuvant setting, require large sample sizes (several thousand patients) and a very strict selection of the patient population (tumors amplifying the HER2 gene). Success in a timely fashion requires global collaboration, dedication to high-standard clinical research, and awareness of all available protocols by oncologists and patients with breast cancer.

Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer.

PURPOSE: This pilot phase II study investigated the efficacy and toxicity of docetaxel with doxorubicin and cyclophosphamide (TAC) as first-line chemotherapy for anthracycline-naive patients with metastatic breast cancer. PATIENTS AND METHODS: Fifty-four patients received a total of 359 courses consisting of docetaxel 75 mg/m2 given intravenously (IV) over 1 hour, preceded by IV doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for a maximum of eight 3-week cycles. RESULTS: After an independent panel review, the overall objective response rate was 77% (complete response, 6%). Overall objective response rates in patients with visceral, bone, and liver involvement were 82%, 82%, and 80%, respectively. Median duration of response was 52 weeks, and median time to progression was 42 weeks. With a median follow-up of 32 months, the median survival had not yet been reached, whereas the 2-year survival was 57%. The main toxicities were hematologic (neutropenia grade 3/4 in 100% of patients and 95% of cycles; febrile neutropenia in 34% of patients and 9% of cycles). Documented grade 3 infection was seen in one patient (2%) in one cycle, and no toxic death was reported. Severe acute or chronic nonhematologic adverse events were infrequent, and docetaxel-specific toxicities (such as fluid retention and nail changes) were mild, with only one patient being discontinued for fluid retention. Congestive heart failure was seen in two patients (4%). CONCLUSION: TAC is an active and manageable regimen that has been chosen as the basis of five randomized phase III trials, including two pivotal studies comparing TAC to fluorouracil plus doxorubicin and cyclophosphamide in the metastatic and adjuvant treatment of breast cancer.

Concurrent weekly carboplatin and radiotherapy for nasopharyngeal carcinoma: report of a joint phase II study.

We report a phase I/II study of weekly concurrent carboplatin and radiotherapy in patients with nasopharyngeal carcinoma (M0 stage). Of 47 patients registered, 45 completed the treatment course. Twenty-six (55%) (95% CI, 41-69%) patients experienced > or =grade 3 acute toxicity (RTOG). Five (11%) (95% CI, 2-20%) patients experienced > or =grade 3 chronic toxicity. This regimen appears to have acceptable toxicity compared to the experimental arm of Phase III Intergroup Study 0099, but progression-free and overall survival are probably inferior. At present, there is no data to suggest that carboplatin can replace cisplatin for concurrent chemoradiation for NPC.

Responsiveness of the EuroQol in breast cancer patients undergoing high dose chemotherapy.

OBJECTIVE: To assess the responsiveness of the EuroQol (EQ-5D) by comparing it with the Functional Living Index-Cancer (FLIC) and a self-reported rating of health-related quality of life (HRQL). METHODS: HRQL was measured four times during the course of high dose chemotherapy (HDC) and bone marrow transplantation in 40 patients with stage II and III breast cancer. Measurements were at baseline (T1), pre-HDC (T2), 3 weeks post-HDC (T3), and 3 months post-HDC (T4). RESULTS: Effect size ranged from 1.16 (T1-T3) to 0.66 (T3-T4) for the EQ-5D and 0.85-0.91 respectively for the FLIC. No significant differences in effect sizes between the EQ-5D and the FLIC were found. Repeated measures ANOVA yielded a significant change for all measures, with HRQL decreasing post-HDC and returning to baseline levels by 3 m post-HDC. EQ-5D dimensions changed significantly over time for mobility, self-care, and usual activities. EQ-5D index scores at T3 had a bimodal distribution. Interpretation of psychological changes was facilitated by an analysis of FLIC items. CONCLUSIONS: The EQ-5D is responsive to the clinically large changes associated with HDC in breast cancer patients. The bimodal distribution of the EQ-5D index has implications for the interpretation of EQ-5D change scores.